CN1451007A - Adenosine A2A receptor antagonists - Google Patents

Adenosine A2A receptor antagonists Download PDF

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CN1451007A
CN1451007A CN01813449A CN01813449A CN1451007A CN 1451007 A CN1451007 A CN 1451007A CN 01813449 A CN01813449 A CN 01813449A CN 01813449 A CN01813449 A CN 01813449A CN 1451007 A CN1451007 A CN 1451007A
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alkoxyl group
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phenyl
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CN1247588C (en
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B·R·纽斯塔德特
N·A·林多
W·J·格林李
D·图尔施安
L·S·西尔弗曼
夏岩
C·D·博伊尔
S·查卡拉曼尼尔
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Merck Sharp and Dohme LLC
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Schering Corp
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
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    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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    • A61P25/00—Drugs for disorders of the nervous system
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Abstract

Compounds having the structural formula (I) or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted phenyl, cycloalkenyl, or heteroaryl; X is alkylene or -C(O)CH2-;Y is -N(R<2>)CH2CH2N(R<3>)-, -OCH2CH2N(R<2>)-, -O-, -S-, -CH2S-, -(CH2)2-NH-, or optionally substituted,(Ia), m and n are 2-3, and Q is nitrogen or optionally substituted carbon; and Z is optionally substituted phenyl, phenylalkyl or heteroaryl, diphenylmethyl, R<6>-C(O)-, R<6>-SO2-, R<6>-OC(O)-, R<7>-N(R<8>)-C(O)-, R<7>-N(R<8>)-C(S)-, phenyl-CH(OH)-, or phenyl-C(=NOR<2>)-; or when Q is CH, (Ib),phenylamino or pyridylamino; or Z and Y together are substituted piperidinyl or substituted phenyl; and R<2>, R<3>, R<6>, R<7>, and R<8> are as defined in the specification are disclosed, their use in the treatment of Parkinson's disease, alone or in combination with other agents for treating Parkinson's disease, and pharmaceutical compositions comprising them; also disclosed are a processes for preparing intermediates useful for preparing compounds of formula (I).

Description

Adenosine A 2aReceptor antagonist
Technical field
5-amino-the pyrazolo that the present invention relates to replace-[4,3-e]-1,2,4-triazolo [1,5-c] pyrimidine adenosine A 2aThe application in treatment central nervous system disease, particularly Parkinson's disease of receptor antagonist and described compound, and the pharmaceutical composition that comprises described compound.The invention still further relates to preparation 5-amino-2-(replacement) pyrazolo-[4,3-e]-1,2, the method for 4-triazolo [1,5-c] pyrimidine (being used to prepare the intermediate of The compounds of this invention).
Background technology
Adenosine is known to be the endogenous conditioning agent of many physiological functions.On the level of cardiovascular systems, adenosine is strong vasodilator and cardioinhibitor.To central nervous system, adenosine has the calmness of inducing, anxiety and anti-epileptic effect.To respiratory system, adenosine can be induced bronchoconstriction.In the kidney level, it plays a kind of biphasic effect, the vasodilation when vasoconstriction when comprising lower concentration and high dosage.Adenosine plays the effect of fat splitting inhibitor and thrombocyte is played the poly-effect of anti-freezing adipocyte.
The effect of adenosine by means of with different film specific receptorss between interaction and carry out, these acceptors belong to the receptor family that is coupled together with G protein.Biological chemistry and pharmaceutical research can have been discerned the Adenosine Receptors of at least 4 subclass: A together with the progress of molecular biology aspect 1, A 2a, A 2bAnd A 3A 1And A 3Be high affinity, the activity of inhibitory enzyme adenylate cyclase; And A 2aAnd A 2bBe to hang down affinity, excite the activity of this enzyme.As antagonist energy and A 1, A 2a, A 2bAnd A 3The neplanocin of acceptor interaction is also found out.
Because side effect is little, so to A 2aAcceptor selectively antagonist has pharmacological significance.In central nervous system, A 2aAntagonist has antidepressive character and can excite cognitive function.In addition, data presentation, A 2aAcceptor is present in the substrate knot with high-density, known the controls movement aspect is played an important role.Here, A 2aAntagonist can improve because of the caused motor damage of the nerve degeneration disease such as Parkinson's disease, senile dementia such as Alzheimer ' s disease and organic psychosis.
Some compound relevant with xanthine it is found that it is A 1The selective antagonist of acceptor, and some xanthine and non-Xanthine compounds it is found that to have with respect to A in varying degrees 1With A 2aHigh A 2aAffinity.Be disclosed in triazolo-pyrimidine adenosine A that the 7-position has different substituents before this 2aReceptor antagonist, for example at WO95/01356, US5,565,460, among WO97/05138 and the WO98/52568.
Summary of the invention
The present invention relates to have compound in structural formula I Or its drug acceptable salt, wherein
R is R 1-furyl, R 1-thienyl, R 1-pyridyl, R 1-pyridyl N-oxide compound, R 1-oxazolyls, R 10-phenyl, R 1-pyrryl or C 4～C 6Cycloalkenyl group;
X is C 2～C 6Alkylidene group or-C (O) CH 2-;
Y is-N (R 2) CH 2CH 2N (R 3)-,-OCH 2CH 2N (R 2)-,-O-,-S-,-CH 2S-,-(CH 2) 2-NH-or
Figure A0181344900112
And
Z is R 5-phenyl, R 5-phenyl (C 1～C 6) alkyl, R 5-heteroaryl, diphenyl methyl, R 6-C (O)-, R 6-SO 2-, R 6-OC (O)-, R 7-N (R8)-C (O)-, R 7-N (R 8)-C (S)-,
Figure A0181344900113
, phenyl-CH (OH)-or phenyl-C (=NOR 2)-; Perhaps working as Q is The time, Z also can be phenyl amino or pyridinylamino; Perhaps
Z with Y is
R 1Be 1～3 substituting group, be independently selected from hydrogen, C 1～C 6-alkyl ,-CF 3, halogen ,-NO 2,-NR 12R 13, C 1～C 6Alkoxyl group, C 1～C 6Alkylthio, C 1～C 6Alkyl sulphinyl and C 1～C 6Alkyl sulphonyl;
R 2With R 3Be independently selected from hydrogen and C 1～C 6Alkyl;
M and n are 2～3 independently;
Figure A0181344900122
Or
Figure A0181344900123
Q is
R 4Be 1～2 substituting group, be independently selected from hydrogen and C 1～C 6Alkyl or two R on same carbon atom 4Substituting group can form=O;
R 5Be 1～5 substituting group, be independently selected from hydrogen, halogen, C 1～C 6-alkyl, hydroxyl, C 1～C 6Alkoxyl group ,-CN, two-((C 1～C 6) alkyl) amino ,-CF 3,-OCF 3, ethanoyl ,-NO 2, hydroxyl (C 1～C 6) alkoxyl group, (C 1～C 6)-alkoxyl group (C 1～C 6) alkoxyl group, two-((C 1～C 6)-alkoxyl group) (C 1～C 6) alkoxyl group, (C 1～C 6)-alkoxyl group (C 1～C 6) alkoxyl group-(C 1～C 6)-alkoxyl group, carboxyl (C 1～C 6)-alkoxyl group, (C 1～C 6)-carbalkoxy (C 1～C 6) alkoxyl group, (C 3～C 6) cycloalkyl (C 1～C 6) alkoxyl group, two ((C 1～C 6)-alkyl) amino (C 1～C 6) alkoxyl group, morpholinyl, (C 1～C 6) alkyl-SO 2-, (C 1～C 6) alkyl-SO-(C 1～C 6) alkoxyl group, THP trtrahydropyranyl oxygen base, (C 1～C 6) alkyl-carbonyl (C 1～C 6)-alkoxyl group, (C 1～C 6)-carbalkoxy, (C 1～C 6) alkyl-carbonyl oxygen base (C 1～C 6)-alkoxyl group ,-SO 2NH 2, phenoxy group,
Figure A0181344900124
Or adjacent R 5Substituting group lumps together and is-O-CH 2-O-,-O-CH 2CH 2-O-,-O-CF 2-O-or-O-CF 2CF 2-O-and the carbon atom that is connected with them constitute a ring;
R 6Be (C 1～C 6) alkyl, R 5-phenyl, R 5-phenyl (C 1～C 6) alkyl, thienyl, pyridyl, (C 3～C 6)-cycloalkyl, (C 1～C 6) alkyl-OC (O)-NH-(C 1～C 6) alkyl-, two-((C 1～C 6) alkyl) aminomethyl or (C 1-C 6) alkyl
Figure A0181344900131
R 7Be (C 1～C 6) alkyl, R 5-phenyl or R 5-phenyl (C 1～C 6) alkyl;
R 8Be hydrogen or C 1～C 6Alkyl; Perhaps R 7With R 8Be together-(CH 2) p-A-(CH 2) q, wherein p and q are 2 or 3 independently, A be chemical bond ,-CH 2-,-S-or-O-and the nitrogen-atoms that is connected with them constitute a ring;
R 9Be 1～2 group, be independently selected from hydrogen, C 1～C 6Alkyl, hydroxyl, C 1～C 6Alkoxyl group, halogen ,-CF 3(C 1～C 6) alkoxyl group (C 1～C 6) alkoxyl group;
R 10Be 1～5 substituting group, be independently selected from hydrogen, halogen, C 1～C 6Alkyl, hydroxyl, C 1～C 6Alkoxyl group ,-CN ,-NH 2, C 1～C 6Alkylamino, two-((C 1～C 6) alkyl) amino ,-CF 3,-OCF 3With-S (O) 0～2(C 1～C 6) alkyl;
R 11Be hydrogen, C 1～C 6Alkyl, phenyl, benzyl, C 2～C 6Alkenyl, C 1～C 6Alkoxyl group (C 1～C 6) alkyl, two-((C 1～C 6) alkyl) amino (C 1～C 6) alkyl, pyrrolidyl (C 1～C 6) alkyl or piperidino-(1-position only) (C 1～C 6) alkyl;
R 12Be hydrogen or C 1～C 6Alkyl; And
R 13Be (C 1～C 6) alkyl-C (O)-or (C 1～C 6) alkyl-SO 2-.
Preferred compound of formula I is those, and wherein R is R 1-furyl, R 1-thienyl, R 1-pyrryl or R 10-phenyl, more preferably R 1-furyl.R 1Hydrogen or halogen preferably.Another kind of preferred compound is that wherein X is an alkylidene group, preferably those of ethylidene.Y preferably
Figure A0181344900132
Wherein Q is
Figure A0181344900133
Or , Q nitrogen preferably wherein.Preferably, each is 2 for m and n, R 4Be hydrogen.The preferred definition of Z is R 5-phenyl, R 5-heteroaryl, R 6-C (O)-or R 6-SO 2-.R 5Preferably hydrogen, halogen, alkyl, alkoxyl group, hydroxy alkoxy base or alkoxyl group alkoxyl group.R 6R preferably 5-phenyl.
The present invention is a kind of pharmaceutical composition on the other hand, and it is included in the compound of Formula I of the treatment significant quantity in the drug acceptable carrier.
Another aspect of the present invention is the treatment central nervous system disease, as depression, cognitive illnesses and nerve degeneration disease such as parkinsons disease, organic senile dementia or psychosis, and the method for apoplexy, comprise the compound of taking general formula I to the Mammals of this kind of needs treatment.Particularly, the present invention relates to treat the method for parkinsons disease, comprise the compound of taking general formula I to the Mammals of this kind of needs treatment.
Another aspect of the present invention is 5-amino-2-(R-replaces)-pyrazolo-[4,3-e]-1,2 of preparation general formula I I, the method for 4-triazolo [1,5-c] pyrimidine, and this compound is the useful intermediates of preparation compound of Formula I.The compound of general formula I I is:
Figure A0181344900141
Wherein R is by top regulation, and its preparation method comprises:
(1) in dimethyl formamide (DMF), uses POCl 3Handle 2-amino-4, the 6-dihydroxy-pyrimidine To obtain 2-amino-4,6-dichloro pyrimidine-5-formaldehyde
Figure A0181344900143
(2) be H with general formula 2The hydrazides of N-NH-C (O)-R is handled aldehyde VII, and wherein R is by top regulation, and the result obtains
(3) intermediate of general formula VIII is handled with hydrazine hydrate and is generated the pyrazolo ring, thereby obtains the intermediate of general formula I X
Figure A0181344900151
And
(4) reset the desired general formula I I compound of generation by dehydration.
The intermediate dehydration that a preferred aspect of this method is general formula I X is reset to obtain 5-amino-2-(R-replacement)-pyrazolo-[4,3-e]-1,2 of general formula I I, 4-triazolo [1,5-c] pyrimidine.The preferred embodiment of this method adopts 2-furancarboxylic acid hydrazides or 2-thiophene hydrazides in step 2, R is the general formula I I compound of 2-furyl or 2-thienyl thereby make wherein.
Another aspect of the present invention is 7-bromine alkyl-5-amino-2-(R-replaces)-pyrazolo [4,3-e]-1,2 of preparation general formula III a, 4-triazolo [1,5-c] pyrimidine, and it is the useful intermediates of preparation compound of Formula I.Preparation general formula III a compound Wherein R is by top regulation, and its method comprises,
(1) muriate of general formula VIII
Figure A0181344900153
With general formula HO-(CH 2) r-NHNH 2The hydroxyalkyl hydrazine handle, wherein r is 2～6, the result obtains
Figure A0181344900154
(2) intermediate of general formula X is reset and cyclisation by dehydration, and the result obtains the three ring intermediates of general formula X I
(3) oxy-compound of general formula X I is converted into the bromide of general formula III a.
Another aspect of the present invention is with the compound of general formula I and one or more are known the useful medicament of treatment parkinsons disease to be cooperated the method for the treatment of parkinsons disease, and the medicine that wherein is used for example is: Dopamine HCL; The Dopamine HCL gaonist; Oxidase inhibitor, Type B (MAO-B); DOPA decarboxylase inhibitor (DCI); Or catechol-O-methyltransferase (COMT) inhibitor.Also disclose a kind of pharmaceutical composition, it comprises, and in drug acceptable carrier, compound of Formula I and one or more are known to the useful medicament of treatment parkinsons disease.
Detailed Description Of The Invention
Term used herein " alkyl " comprises straight or branched.Alkylidene group refers to the divalent alkyl group, also contains straight or branched similarly.Cycloalkylidene is meant the divalent cycloalkyl group.Cycloalkenyl group is meant the C that comprises two keys 4～C 6Naphthenic ring.
Heterocycle is meant monocycle, dicyclo or the benzo-fused heteroaryl groups of certain 5～10 atoms, is made up of 2～9 carbon atoms and 1～4 heteroatoms that is independently selected from N, O and S, and condition is that this ring does not comprise adjacent oxygen and/or sulphur atom.In the N-oxide compound of ring nitrogen class is also included within.The example of bicyclic heteroaryl is pyridyl, oxazolyl, isoxazolyl, oxadiazole base, furyl, pyrryl, thienyl, imidazolyl, pyrazolyl, tetrazyl, thiazolyl, isothiazolyl, thiadiazolyl group, pyrazinyl, pyrimidyl, pyridazinyl and triazolyl.The example of bicyclic heterocyclic group is phthalazinyl (for example, 1,5 or 1,7), imidazole pyridyl, piperidines also [2,3] imidazolyl, piperidines and pyrimidyl and 7-azaindolyl.The example of benzo-fused heteroaryl groups is indyl, quinolyl, isoquinolyl, phthalazinyl, benzothienyl (that is thianaphthenyl), benzimidazolyl-, benzofuryl, benzoxazolyl and cumarone azanyl.All positional isomerss are all at the row of consideration, for example, and 2-pyridyl, 3-pyridyl and 4-pyridyl.R 5The heteroaryl of-replacement refers to such group, and wherein commutable ring carbon atom has the substituting group as stipulating above.
Some compound of the present invention can different stereoisomeric forms in any ratio (for example, enantiomer, diastereomer and atropisomerrism body) exist.The present invention includes all these steric isomers, both comprised the pure mixture that also comprises, comprise racemic mixture.
Some compound will have acid essence, for example, have those compounds of carboxyl or phenolic hydroxyl group group.These compounds can form drug acceptable salt.The example of this kind salt can comprise sodium, potassium, calcium, aluminium, gold and silver salt.Also consider the salt that forms with medicine acceptable amine such as ammonia, alkylamine, hydroxyalkyl amine, N-methylglucosamine and so on.
Some basic cpd also can form drug acceptable salt, for example, and acid salt.For example, pyridine-nitrogen-atoms can generate salt with strong acid, and the compound with the alkali subtituent such as amino group also can generate salt with weak acid.The example that is suitable for living salifiable acid is hydrochloric acid, sulfuric acid, phosphoric acid, acetate, citric acid, oxalic acid, propanedioic acid, Whitfield's ointment, oxysuccinic acid, fumaric acid, succsinic acid, xitix, toxilic acid, methylsulfonic acid or other inorganic and carboxylic acids well known to those skilled in the art.The acid that salt can require by its free alkali form and capacity in a conventional manner contacts and generates.By handling the renewable free alkali form of this salt with suitable dilute alkaline aqueous solution such as dilute sodium hydroxide, salt of wormwood, ammoniacal liquor and sodium bicarbonate.Free alkali form is in some physical properties, and as some is different from its salt form separately on the solubleness in polar solvent, but these bronsted lowry acids and bases bronsted lowry salt in other respects then are equivalent to its free alkali form separately with regard to the object of the invention.
In the drug acceptable salt that all these bronsted lowry acids and bases bronsted lowry salt all should be included in the scope of the present invention; And all bronsted lowry acids and bases bronsted lowry salt are all regarded the free form that is equivalent to respective compound as with regard to the object of the invention.
The compound of general formula I can prepare from starting raw material by currently known methods, and this raw material is known in this area or can be prepared by methods known in the art; For example referring to, WO95/01356 and " J.Med.Chem. (medical chemistry magazine) " 39 (1996) 1164～1171.
Preferably, the compound of general formula I prepares according to method shown in the following reaction scheme.In route 1,5-amino-pyrazolo of general formula I I-[4,3-e]-1,2, the alkylation of 4-triazolo [1,5-c] pyrimidine is used to prepare compound of Formula I: route 1:
Figure A0181344900181
The raw material of general formula I I can with diol ester of two (toluenesulphonic acids) alkyl and the alkali such as NaH, such as dimethyl formamide (DMF), reacting in the inert solvent, perhaps under conditions of similarity, react, obtain the intermediate of the alkyl replacement of general formula III with chloro-, bromo-or two bromo-alkylates.Subsequently, the amine of the compound of general formula III and general formula Z-Y-H reacts in inert solvent such as DMF, under the temperature that improves and generates the compound of general formula I a, that is, X wherein is the compound of Formula I of alkylidene group.
Alternatively, the raw material of general formula I I can with the compound of general formula Z-Y-X-Cl and such as NaH alkali in inert solvent such as DMF, react and generate the mixture that the compound of Formula I that replaced by 7-and the compound of corresponding 8-replacement are formed.
Preparing contained Y is that piperazinyl and Z are R 6-C (O)-, R 6-SO 2-, R 6-OC (O)-, R 7-N (R 8)-C (O)-or R 7-N (R 8)-C (S)-compound of Formula I, can be that the compound of Formula I deprotection of 4-tert-butoxycarbonyl-1-piperazinyl forms by containing Z-Y, for example react by acid with all example hydrochloric acids and so on.The free piperazinyl compound IV that generates, according to the technical routine processes of knowing, the result obtains desired compound.Following route 2 has been summarized this kind program:
Route 2:
Figure A0181344900191
The method representation of another kind of preparation compound of Formula I is in route 3:
Route 3:
In this program, chlorine pyrazolo-pyrimidine V and general formula are that the compound of Z-Y-X-Cl reacts the intermediate of generation and general formula H according to the mode of the alkylation program that is similar to route 1 2N-NH-C (O)-R (or and hydrazine hydrate, subsequently with the compound of general formula C1-C (O)-R) react.The hydrazides that generates rearrangements of dewatering, for example, by N, O-is two-combination of (trimethyl silyl) ethanamide (BSA) or BSA and hexamethyldisilazane (HMDS), processing under intensification.
Raw material is knownly maybe can prepare by methods known in the art.Yet, the compound of general formula I I preferably adopt above-described and below will be in greater detail novel method prepare.
In the first step of this method,, as described in 1602～1603, in DMF, use POCl as " Helv.Chim.Acta (Switzerland's chemistry journal) " 69 (1986) 3Or SOCl 2Handle 2-amino-4,6-dihydroxy-pyrimidine (VI).This reaction at high temperature preferred about 100 ℃, is carried out about 2～8h, preferably about 5h.
In second step, be H with general formula 2The hydrazides of N-NH-C (O)-R is handled 2-amino-4,6-dichloro pyrimidine-5-formaldehyde (VII), and wherein R is by top regulation, and the result obtains the compound of general formula VIII; The compound of general formula VII and hydrazides are by roughly 1: 1 mol ratio use, and preferred hydrazides is excessive a little.Be reflected at room temperature or the highest about 80 ℃ such as CH 3Carry out in the solvent of CN or DMF and so on.Reaction times is about 16h (for example, spending the night).
In the 3rd step, the compound of general formula VIII and 1～5 equivalent hydrazine hydrate are such as CH 3In the solvent of CN or DMF and so on, 60～100 ℃ the heating 1～24h, the result obtains the compound of general formula I X.
In last step, the compound of general formula I X passes through with the mixture of HMDS and BSA or only handles with BSA the dehydration rearrangement takes place.This is reflected under the temperature of raising, preferred about 120 ℃ of about 16h (for example, spending the night).
After each step of this method, thick material adopts traditional method, and for example extraction and/or recrystallization are purified.
Compare with the disclosed method for preparing general formula I I intermediate in the past, the step that this method needs is few, and than carrying out under the mild reaction conditions, and yield is much higher.
The compound of general formula V and VII is known (" Helv.Chim.acta " 69 (1986), 1602～1603).
In the method representation route 4 below of another kind of preparation compound of Formula I.Route 4:
Figure A0181344900211
Muriate VIII handles in the inert solvent such as ethanol and under the temperature of room temperature to 100 ℃ with the hydroxyalkyl hydrazine, and the result generates derivative X.This derivatives class is similar to IX and carries out cyclodehydration like that, for example handles with BSA, and the result obtains tricyclic antidepressants XI.Three ring XI are subsequently with PBr 3Under 80 ℃～150 ℃ raising temperature, handle 1～24h, thereby be converted into bromide IIIa.Intermediate X I also can be converted into tosylate by with toluene sulfonyl chloride and alkaline purification with being similar to IIIa.Bromide IIIa is as above in the face of the described compound that is converted into general formula I like that of III.
In the method representation route 5 below of the compound of another kind of preparation general formula I:
Route 5:
Route 1 is such according to being similar to, and muriate V is converted into alkylating compounds X II, and the latter further reacts with carbazates XIV, the preferably tertiary butyl or benzyl of R ' wherein, and the result obtains derivative XIII.Solvent such as DMF can use under 60～120 ℃ temperature.As reacting at route 1, the result obtains XV to this material subsequently.Then, remove R ' group, for example remove tertiary butyl group with HCl or TFA, the result obtains hydrazine XVI.XVI becomes XVII through acidylate, and the latter is as above-described cyclodehydration, and the result obtains desired Ia.Alternatively, XII can react with hydrazides XVIII and obtain XIX, and the latter is converted into XVII by the preparation that is similar to XV.
Adopt above program, prepared following compounds.
Preparation 1
Figure A0181344900231
Step 1: drip DMF (17.8mL, in the time of 0.23mol), POCl 3(84mL 0.9mol) stirs and is cooled to 5～10 ℃.Allow mixture be warmed to room temperature (RT), and mark part adding 2-amino-4,6-dihydroxy-pyrimidine VI (14g, 0.11mol).At 100 ℃ of heating 5h.Under vacuum, boil off unnecessary POCl 3, resistates is poured in the frozen water, and is stirred and spend the night.Solid collected by filtration and from cross filterable ethyl acetate (EtOAc) solution recrystallization go out this dried material, the result obtains this aldehyde VII, 230 ℃ of fusing points.Mass spectrum: M+=192, and PMR (DMSO): δ 8.6 (δ, 2H); δ 10.1 (s, 1H).
Step 2: (0.38g, 2mmol) (0.31g 2.5mmol) is containing N to the product mixtures of step 1, N-diisopropylethylamine (0.44mL, CH 2.5mmol) with 2-furancarboxylic acid hydrazides 3Stir among the CN (50mL), under the RT and spend the night.From reaction mixture, boil off solvent, and resistates is distributed between ethyl acetate and the water layer.Organic layer removes with dried over mgso and desolvates, and resistates is from CH 3Recrystallization among the CN, the result generates desired compound VIII.Mass spectrum: MH+=282.
Step 3: (75mg 1.5mmol) joins step 2 product (0.14g, CH 0.5mmol) to hydrazine hydrate 3In the CN hot solution.Backflow 1h.Be cooled to room temperature and collect yellow product IX.Mass spectrum: MH+=260.
Step 4: the product of step 3 (5.4g, 0.021mol) at hexamethyldisilazane (100mL) and N, in the mixture of two (trimethyl silyl) ethanamides (35mL) of O-120 ℃ of heated overnight.Remove volatile component under vacuum, resistates is made into slurry in hot water, and the result obtains solid precipitation.From 80% acetic acid aqueous solution, produce target compound behind the recrystallization.Fusing point＞300 ℃.Mass spectrum: MH+=242.
Preparation 2
Figure A0181344900241
Preparation 1 product (6.0g, 25mmol), two (tosylates) of ethylene glycol (11.1g, 30mmol) and NaH (60% in oil, 1.19g, 30mmol) merging in dry DMF (30mL).At N 2Under stir 24h, filter the back obtain cream-colored solid target compound (PMR is in DMSO: δ 4.47+4.51 triplet, 8.03s).Filtrate is handled through the chromatogram art and is isolated additional material.
Preparation 3
Figure A0181344900242
According to the mode that is similar to preparation 1, but adopt 2-thiophene hydrazides, preparation yellow solid target compound, mass spectrum: MH+=258.
Preparation 4
Figure A0181344900243
According to the mode that is similar to preparation 2, prepare 3 product but adopt, preparation yellow solid target compound, PMR (DMSO) δ 4.49+4.49+4.54 triplet, 8.05s.
Preparation 5
Aryl piperazines
1-(2,4 difluorobenzene base) piperazine is by 2, and the 4-difluoro bromobenzene prepares.This bromide (8.0g, 41.4mmol), piperazine (21.4g, 249mmol), sodium tert-butoxide (5.6g, 58mmol) and BINAP (1.55g 2.5mmol) in the system of toluene (20mL), adds Pd 2(dba) 3(0.477g, 0.83mmol).Mixture under nitrogen atmosphere, 110 ℃ the heating 20h.Treat its cooling, and extract with 1N HCl.Extract alkalizes to pH=10 with sodium hydroxide, then with CH 2Cl 2Extraction, dry and concentrated back obtains brown oily target compound.
In a comparable manner, prepare following aryl piperazines (Me is a methyl):
Figure A0181344900251
1-(5-ethyl-2-pyrimidyl) piperazine is prepared by 2-chloro-5-ethyl-pyrimidine.This muriate (2.0g, 14mmol) and piperazine (3.0g is 35mmol) in ethanol (70mL), heat 2h in 90 ℃, encloses container.Concentrate and at CH 2Cl 2And distribute between the 2N sodium hydroxide.Organic layer also concentrates with dried over mgso.Crude product is at the enterprising circumstances in which people get things ready for a trip spectrum of silica gel purification (CH 2Cl 2-CH 3OH), the result obtains the yellow oily piperazine.
In a similar way, prepare following piperazine by suitable muriate:
1-(4-cyano group-2-fluorophenyl) piperazine, by 3, the preparation of 4-difluoro benzonitrile.This nitrile (2.0g, 14.4mmol), piperazine (6.2g, 72mmol) and salt of wormwood (2.4g, 17mmol) reflux 22h in toluene.Treat its cooling, and with the 1N hcl as extraction agent.Alkalize to pH=10 with sodium hydroxide.With CH 2Cl 2Extraction also washes with water, uses the salt water washing then.Organic layer is with dried over mgso and concentrate acquisition white solid piperazine.
By similar mode, prepare following piperazine (Et is an ethyl) by suitable fluorochemical:
Figure A0181344900262
1-(4-(2-methoxy ethoxy) phenyl) piperazine is by 4-(4-hydroxyl-phenyl)-1-acetylpiperazine preparation.To be dissolved with NaN (60% in mineral oil, 0.79g, among DMF 20mmol) (25mL), add phenol (3.0g, 13.6mmol), add subsequently the 2-bromo-ethyl-methyl ether (2.27g, 16.3mmol).At stirring at room 18h, concentrate and between ethyl acetate and 5% citric acid, distribute.Organic phase is used the salt water washing then with the washing of 1N sodium hydroxide.With dried over mgso and concentrated, the result obtains the white solid alkylate.This material (2.2g, 7.9mmol) reflux 1h in 6N hydrochloric acid (30mL).Treat its cooling and alkalize to pH=10 with sodium hydroxide.With CH 2Cl 2Extraction also washes with water, uses the salt water washing again.Organic phase also concentrates with dried over mgso, as a result output yellow oily piperazine.
(except that the cyclopropyl methyl ether is adopted the alkaline hydrolysis) prepares following piperazine in a similar manner:
4-(2-methylamino-oxyethyl group) fluorobenzene is by 4-(2-bromo-oxyethyl group)-fluorobenzene preparation.In encloses container, (1.0g is 4.6mmol) at CH for bromide 3Among the OH (5mL) with CH 3NH 2At CH 3(2M, 46mL 92mmol) merge among the OH.At 60 ℃ of heating 18h, concentrate and between ethyl acetate and saturated sodium bicarbonate, distribute.Organic phase with dried over mgso and concentrated, obtains yellow oily amine with the salt water washing.
(4-(2-methoxy ethoxy) ethamine divides two step preparations to N-methyl-2-.4-(2-methoxy ethoxy) phenol (1.68g, 10.0mmol), 1, the 2-methylene bromide (16.9g, 90mmol) and salt of wormwood (2.76g is 20mmol) at CH 3Merge among CN (20mL) and the DMF (10mL).Reflux 22h treats its cooling, filters, and at ether (Et 2O) and between the 1N sodium hydroxide distribute.With the salt water washing, with dried over mgso and concentrated, the result obtains beige solid Bromomethyl methyl ether.(0.97g is 3.5mmol) with 2M CH for this solid 3NH 2/ CH 3OH (35mL) merges.Heating in airtight test tube (65 ℃ 18h), concentrate and distribute between ether and 1N sodium bicarbonate.With the salt water washing, with dried over mgso and concentrated, the result obtains orange oily amine.
1-phenyl-2-piperazine ketone is by 4-benzyloxycarbonyl-1-phenyl-2-piperazine ketone preparation.(1.61g 5.2mmol) merges in ethanol (50mL) and 1N hydrochloric acid (6N) with 10%Pd/C (0.4g) this raw material.Hydrogenation 2h and filtration under 45psi.Resistates on silica gel (with CH 2Cl 2: CH 3OH: NH 4OH is an elutriant) the chromatogram purification, the result obtains cream-colored solid piperazine ketone.
Preparation 6
Figure A0181344900281
Step 1: (0.56g 2.0mmol) is dissolved in hot CH to the product of step 2 in the preparation 1 3Among the CN (200mL).Adding 2-hydroxyethylhydrazine (0.51g, 6.0mmol).Heating 2h and concentrated under refluxing.With 25mL water treatment and stirring, the result obtains a kind of solid.Collect and drying, obtain alcohol, MS:m/e=304 (M+1).
Step 2: the product of step 1 (0.10g, 0.33mmol) in BSA (10mL), 115 ℃ of following heating 4h.Concentrate in a vacuum, and wash with aqueous methanol.Collect and dry back acquisition crystallized product MS:m/e=286 (M+1).
Step 3: the product of step 2 (0.285g, 1.0mmol) and PBr 3(2.0mL 21mmol) merges.At 145 ℃ of heating 2h, cooling pours on ice.Filter and dry this solid.Recrystallization from methyl alcohol, the result obtains target compound, MS:m/e=348+350 (M+1).
Preparation 7
Figure A0181344900282
5-bromo-2-furancarboxylic acid (0.50g, 2.6mmol) and sodium bicarbonate (0.44g 5.2mmol) merges in hexane (6mL) and water (5.2mL).Add Selectfluor (0.98g, 2.8mmol) and stir 2h.Isolate hexane layer and use dried over mgso, result to obtain the solution of 2-bromo-5-fluoro furans.Dilute and be cooled to-78 ℃ with THF (6mL).Adding 2.5M n-Butyl Lithium/hexane (4.2mL, 11mmol).Stir 10min, add excessive dry ice, restir 1h.With the acid treatment of 1N salt, with CH 2Cl 2Extraction, and use dried over mgso.Concentrate and drying, the result obtains the white solid target compound, PMR (CDCl 3) δ 6.70+7.28.
Embodiment 1
Figure A0181344900291
(0.55g, 1.25mmol) (0.50g 2.5mmol) merges in DMF (7mL) tosylate of preparation 2, at 80 ℃ of heating 20h with 1-(2,4 difluorobenzene base) piperazine.Concentrate and by flash distillation column chromatography art processing (CH 2Cl 2, CH 3OH+NH 3) result obtains cream-colored solid target compound, mass spectrum m/e=466 (M+H).
In a similar manner, preparation following compounds:
Figure A0181344900301
Figure A0181344900311
Figure A0181344900331
Figure A0181344900351
Figure A0181344900361
Figure A0181344900371
Figure A0181344900381
Embodiment 2 Step 1:
Figure A0181344900401
Preparation 1 product (0.60g, 2.5mmol), 1, the 3-dibromopropane (0.60g, 3.0mmol) and NaH (60% in oil, 0.119g, 3.0mmol) merging in dry DMF (9mL).Under nitrogen atmosphere, stir 2h, concentrate and process flash chromatography art, obtain solid target compound (PMR, CDCl 3+ CD 3OD: δ 2.43,3.38+4.51, triplet, 8.09s), and the isomer of 8-replacement.
Step 2:
(0.050g, 0.14mmol) (0.045g 0.28mmol) merges in DMF (2mL) product of step 1, and heats 4h at 80 ℃ with the 1-phenylpiperazine.Concentrate and by flash distillation column chromatography art (CH 2Cl 2, CH 3OH+NH 3) purify, the result obtains cream-colored solid target compound, mass spectrum m/e=443 (M+H).
Similarly, preparation following compounds:
Figure A0181344900402
Figure A0181344900403
Embodiment 3
The compound of embodiment 1～2 adopts the follow procedure preparation again:
Preparation 1 product (0.15g, 0.62mmol), 1-phenyl-4-(2-chloroethyl) piperazine (0.17g, 0.75mmol) and NaH (60% in oil, 0.035g, 0.87mmol) merging in dry DMF (7mL).Under nitrogen atmosphere, stir 48h, add additional muriate (0.03g) and NaH (0.005g), and then stir 72h.Concentrate and by flash distillation column chromatography art (CH 2Cl 2, CH 3OH+NH 3) purify, the result obtains cream-colored solid target compound, mass spectrum m/e=429 (M+H).
Similarly, the compound of preparation embodiment 1～3, as following compound:
Figure A0181344900412
Embodiment 4
Figure A0181344900413
Step 1:
1-(2,4 difluorobenzene base) piperazine (1.5g, 7.6mmol), the 2 bromopropionic acid ethyl ester (1.65g, 9.1mmol) and DIPEA (1.1g 8.3mmol) merges in DMF (8mL).Stir 4h, concentrate and between ether and water, distribute.With salt water washing, drying (sal epsom) and concentrated, the result obtains the yellow oily ester, NMR (CDCl 3) stable.
Step 2:
(2.15g 7.2mmol) in the solution of THF (10mL), drips LiAlH at the product of step 1 4(1.0M in THF, 4.4mL, 4.4mmol).At 60 ℃ of heating 1h, add water (0.16mL), 15% sodium hydroxide (0.16mL) adds water (0.49mL) then.Filter and concentrate, obtain yellow oily alcohol, NMR (CDCl 3) stable.
Step 3:
To at 5 ℃ of CH 2Cl 2Step 2 product (10mL) (0.90g, 3.5mmol) in, add SOCl 2(0.38mL, 5.3mmol).Treat that it warms and stirs 16h.Concentrate and at CH 2Cl 2And distribute between the 1N sodium hydroxide, wash with water, dry (sal epsom) also concentrates, and the result obtains the yellow oily crude product.
Step 4: preparation 1 product (0.20g, 0.83mmol), the product of step 3 (0.34g, 1.2mmol) and NaH (60% in oil, 0.040g, 1.0mmol) merging in dry DMF (5mL).At 60 ℃ of heating 24h, add additional muriate (0.15g) and NaH (0.02g), and then heating 4h.Concentrate and by flash distillation column chromatography art (CH 2Cl 2, CH 3OH+NH 3) purify, the result obtains the yellow solid target compound, mass spectrum m/e=479 (M+H).
Similarly, preparation following compounds:
Figure A0181344900422
Embodiment 5
Adopt the program of embodiment 1, with alternative 2 the tosylate for preparing of the tosylate of preparation 4, the preparation following compounds: Embodiment 6
Step 1: (4.17g is 9.2mmol) at CH to the product of embodiment 3-1 2Cl 2In the solution (500mL), add anhydrous hydrogen chloride (120mL4.0M dioxane solution) and stir 2h.Under vacuum, be concentrated into drying and resistates is dissolved in the water.Deprotection product with aqueous sodium hydroxide solution alkalization and collecting precipitation.Mass spectrum: MH+=354.
Step 2: (71mg, 0.2mmol) (51mg, mixture 0.3mmol) are containing N to the product of step 1, and (52mg is among the dry DMF (10mL) 0.4mmol), stir 6h under the room temperature for the N-diisopropylethylamine with the 4-methoxy benzoyl chloride.Solution poured in the water and the target compound of collecting precipitation.Mass spectrum: MH+=488.
In a similar manner, preparation following compounds:
Embodiment 7
At room temperature to embodiment 6, the product of step 1 (53mg, 0.15mmol) in the solution of NMP (10mL), add 4-chloro-phenyl-isocyanic ester (25.3mg, 0.165mmol).Stirring is spent the night, and adds additional 25.3mg isocyanic ester, and restir 1h transforms fully until all raw materials.Pour in the water and the target compound of collecting precipitation.Mass spectrum: MH+=507.
In a similar manner, prepare following compounds by suitable isocyanic ester, lsothiocyanates or urea chloride:
Figure A0181344900453
Figure A0181344900454
Figure A0181344900461
Embodiment 8
With embodiment 6, and the product of step 1 (53mg, 0.15mmol) (77mg makes slurry among the dry DMF (20mL) 0.76mmol) containing triethylamine; Adding 2,4 difluorobenzene SULPHURYL CHLORIDE (37 μ l, 0.225mmol).Stirring at room 2 days.Pour in the water and the target compound of collecting precipitation.Mass spectrum: M+=529.
In a similar manner, preparation following compounds
Figure A0181344900463
Embodiment 9
Figure A0181344900472
(56mg 0.3mmol) joins embodiment 6, and (71mg, 0.2mmol) (101mg is in the slurry of warm DMF (25mL) 1.0mmol) containing triethylamine for the product of step 1 with chloroformic acid 4-p-methoxy-phenyl ester.Mixture is in stirred overnight at room temperature.Solution concentration is poured in the water then to 1/3 of its original volume.Collecting precipitation washes with water, and dry in a vacuum.From CH 3OH/CH 2Cl 2Middle recrystallization obtains target compound.Mass spectrum: MH+=504.
Embodiment 10
Step 1:1-bromo-2,4 difluorobenzene (1.00g, 5.18mmol), N, N '-dimethyl-ethylenediamine (2.74g, 31.1mmol), the NaO-tertiary butyl (0.70g, 7.2mmol), Pd (dba) 2(0.060g, 0.10mmol) (0.19g 0.31mmol) merges in toluene (10mL) with (±)-BINAP.At 110 ℃ of heating 18h, treat its cooling, then with the 1N hcl as extraction agent.The aqueous solution is with the sodium hydroxide alkalization and with CH 2Cl 2Extraction.Dry, concentrate and purify by PLC, the result obtains N-(2,4 difluorobenzene base)-N, N '-dimethyl-ethylenediamine.
Step 2: (0.100g is 0.23mmol) with product (0.091g, the 0.46mmol) merging among DMF (2mL) of step 1 for preparation 2 product.At 80 ℃ of heating 90h, treat its cooling, concentrate and utilize column chromatography to purify, the result obtains the oily target compound, mass spectrum m/e=467.
Embodiment 11
The compound of embodiment 1-2 is by preparing by follow procedure.
Step 1:
Figure A0181344900481
To preparation 1, the product of step 1 (768mg 4mmol) in the solution in DMF (20mL), adds N, the N-diisopropylethylamine (0.88mL, 5mmol), add again hydrazine hydrate (0.2mL, 4.1mmol).Treat that solution warms, solid precipitation dissolves in 1h gradually then.After stirring 3h, solution is concentrated into the about 1/3 of its volume under vacuum, and pours in the water.Collecting precipitation, and at CH 3Recrystallization among the OH, the result obtains the chlorine pyrazolopyrimidine.Mass spectrum: MH+=170.Step 2:
Figure A0181344900482
At 5～10 ℃, (6.5g, 40mmol) (6.4mL is 48mmol) at CH with 50% moisture monochloroacetaldehyde to the 1-phenylpiperazine 2Cl 2In the solution (125mL), mark part adds Na (OAc) 3BH (12.72g, 60mmol).After bubbling stops, allowing mixture be warmed to room temperature, and stir 3h.With CH 2Cl 2(100mL) dilution, and shake until pH with the 1N aqueous sodium hydroxide solution and to be higher than 8.Water and salt water washing organic layer are with dried over mgso and except that desolvating.On silica gel and with 1%CH 3OH/CH 2Cl 2Wash-out carries out chromatogram purifies, and the result obtains target compound.Mass spectrum: MH+=225.Step 3:
In the temperature of ice bath, to 60%NaH (0.14g, 3.5mmol) in the slurry of DMF (30mL), mark part add step 1 product (0.51g, 3mmol).After gas release finishes, add the product of step 2.The mixture that obtains is in stirred overnight at room temperature.Filter the garnet insoluble matter, under vacuum, filtrate is concentrated into drying.With this gumminess resistates and CH 3OH grinds together, and the result obtains the light yellow solid target compound.Mass spectrum: MH+=358.
The product of step 3 is handled in the step 2 and 4 like that as preparation 1, and the result obtains the compound of embodiment 1～2.
Embodiment 12
Step 1: to NaH (60% in oil, and 142mg 3.5mmol) in DMF (15mL), adds embodiment 11, the muriate of step 1 (500mg, 2.9mmol).In this material, add 1-(2-chloroethyl)-4-(2,4 difluorobenzene base) piperazine (846mg, 3.5mmol).At stirring at room 90h and concentrated.After purifying, chromatogram obtains desired white solid compound.
PMR DMSO: δ 2.57 (4H, s), 2.76 (2H, t), 2.85 (4H, s), 4.30 (2H, t), 7.0 (2H, m), 7.15 (1H, dxt), 7.26 (2H, s), 7.97 (1H, s).
Step 2: (37mg, 0.095mmol) (9.2 μ L 0.19mmol) handle the muriate of step 1 with hydrazine hydrate in DMF (95mL).Behind the 4h, concentrate and on PLC chromatogram purification, the result obtains brown oily hydrazine.Mass spectrum: MH+=390.
Step 3: the hydrazine of step 2 (18mg, 0.047mmol) in DMF (2mL) with thiophene-2-carbonyl chloride (5.2 μ L, 0.047mmol) and DIPEA (12.2 μ L 0.07mmol) handle.Behind the 4h, concentrate and on PLC chromatogram purification, the result obtains the yellow oily hydrazides.Mass spectrum: MH+=500.
Step 4: (13mg is 0.026mmol) at N, in two (trimethyl silyl) ethanamides (1mL) of O-, 100 ℃ of heating 2h for the hydrazides of step 3.Concentrate and on PLC chromatogram purification, the result obtains the white solid target compound.Mass spectrum: MH+=482.
Employed 1-in this order (2-chloroethyl)-4-(2,4 difluorobenzene base) piperazine prepares in two steps.At 0 ℃, chloroacetyl chloride (1.76mL, 22.1mmol) and N-methylmorpholine (2.65mL, (3.98g is 20.1mmol) at CH 24.1mmol) to join 1-(2,4 difluorobenzene base) piperazine 2Cl 2In the solution (15mL).At stirring at room 1h, concentrate, between ethyl acetate-water, distribute, dry and concentrated, the result obtains brown oily acid amides.(4.71g 17.1mmol) in the solution of THF (25mL), drips BH to this product of 0 ℃ 3CH 3S/THF (2M, 12.8mL, 25.6mmol).In stirred overnight at room temperature,, concentrate and at CH with the methyl alcohol chilling 2Cl 2Distribute between-the water.Organic layer is dry and concentrated.Crude product is with BH 3CH 3S/THF handles for the second time and carries out aftertreatment as mentioned above, and the result provides brown oily chloroethyl piperazine.
Embodiment 13
Step 1: to NaH (2.14g, 60% in oil, 53mmol) in DMF (20mL), adds embodiment 11, the product of step 1 (7.55g, 45mmol).Adding 1-bromo-2-monochloroethane (14.8mL, 178mmol).Stir 1.5h, and concentrate.After purifying, chromatogram obtains the white solid dichloride.
Step 2: to the product of step 1 (3.7g, 16mmol) in the solution in DMF (20mL), add tert-butyl carbazate (2.53g, 19mmol).At 80 ℃ of heating 18h, and concentrate.After purifying, chromatogram obtains the white solid carbazates.
Step 3: to the product of step 2 (3.16g, 9.6mmol) and KI (1.6g, 9.6mmol) in DMF (25mL), add 1-(2,4 difluorobenzene base) piperazine (3.82g, 19mmol).At 90 ℃ of heating 68h and concentrated.After purifying, chromatogram obtains the brown solid piperazine.
Step 4: (3.38g 6.9mmol) is dissolved in 1: 1CH to the product of step 3 3OH-CH 2Cl 2(50mL).Add the solution in the 4M hydrogenchloride Zai diox (20mL).Stir 16h and add ammoniacal liquor to pH11～12.Concentrate and the chromatogram purification, the result obtains the yellow solid hydrazine.
Step 5: the product of step 4 (0.120g, 0.31mmol) with 5-bromo-2-furancarboxylic acid (0.071g, 0.37mmol) and HOBt.H 2(0.050g 0.37mmol) merges in DMF (6mL) O.Add EDCl (0.071g, 0.37mmol) and stir 1h.Concentrate and chromatogram purification back acquisition yellow solid hydrazides.
Step 6: (0.163g 0.28mmol) is dissolved in N to the product of step 5, in two (trimethyl silyl) ethanamides (6mL) of O-.At 120 ℃ of heating 16h, and pour CH into 3Among the OH.Concentrate and chromatogram purification back acquisition pale solid target compound: MS m/e544+546 (M+1).
Prepare the compound of array structure down similarly, wherein R presses the regulation in the table:
Figure A0181344900522
Embodiment 14
Embodiment 13, the product of step 4 (0.080g, 0.20mmol) with the hydrochloric acid nicotinoyl chlorine (0.044g, 0.25mmol) and diisopropylethylamine (0.086mL 0.49mmol) handles in DMF (4mL).Stir 2h, concentrate and obtain the white solid hydrazides after also chromatogram is purified.
This material is handled with BSA, and as embodiment 13, step 6, result obtain the white solid target compound: MS m/e477 (M+1).
Prepare the compound of array structure down similarly, wherein R presses the regulation in the table:
Figure A0181344900533
Embodiment 15
Step 1: to embodiment 13, the product of step 2 (3.54g, 10.8mmol) and KI (1.79g, 10.8mmol) in DMF (35mL), add 1-(4-(2-methoxy ethoxy) phenyl) piperazine (5.1g, 22mmol).At 90 ℃ of heating 90h and concentrated.After purifying, chromatogram obtains the brown solid piperazine.
Step 2: the product of step 1 is with HCl, and as embodiment 13, step 4 is handled like that, and the result obtains the yellow solid hydrazine.
Step 3: the product of step 2 is with 5-chloro-2-furancarboxylic acid, and as embodiment 13, step 5 is handled like that, and the result obtains the yellow solid hydrazides.
Step 4: the product of step 3 is with BSA, and as embodiment 13, step 6 is handled like that.After purifying, chromatogram obtains white solid target compound, MS m/e538+540 (M+1).
Prepare the compound of array structure down similarly, wherein R presses the regulation in the table:
Figure A0181344900541
Embodiment 16
Figure A0181344900543
(0.080g, 0.16mmol) (0.028mL 0.28mmol) and among 4-Dimethylamino pyridine (0.004g is 0.03mmol) at the D) MF (5mL) merges the product of embodiment 1-83 with ether.Stir 4h, concentrate and the chromatogram purification, obtain the white solid acetic ester, MS:m/e=532 (M+1).
Embodiment 17
The product of embodiment 1-21 (0.100g, 0.21mmol) and H 2(0.029g 0.42mmol) merges in 95% ethanol (9mL) NHOH.HCl.Add 10 concentrated hydrochloric acids, reflux 5h adds DMF (1.5mL), and heating 18h treats its cooling, filters the back and obtains white solid oxime, MS:m/e=487 (M+1).Mother liquor is purified through chromatogram and is obtained additional product.
Prepare its methyloxime similarly, white solid, MS:m/e=501 (M+1):
Figure A0181344900551
Embodiment 18
Step 1: to 4-bromobenzene ethanol (0.600g, 2.98mmol) and 3-pyridyl boric acid (0.734g, 5.97mmol) in the solution of toluene (35mL) and ethanol (9mL), add salt of wormwood (0.8826g, 5.97mmol) solution and four (triphenylphosphine) in water (16mL) close palladium (O) (0.172g, 0.149mmol).In airtight test tube, 120 ℃ the heating 18h, then the cooling.With ethyl acetate extraction, use the salt water washing, dry (salt of wormwood) also concentrates.Silica gel chromatography purifying (30-50% ethyl acetate/hexane) obtains 2-diaryl alcohol.
Step 2: at 0 ℃, (0.540g is 2.71mmol) at CH to the product of step 1 2Cl 2(15mL), add methylsulfonyl chloride (0.35mL, 3.52mmol) and Et 3N (0.57mL, 4.00mmol).Stir 2.5h and with CH 2Cl 2Extraction.Dry (sodium sulfate) also concentrates, and obtains methanesulfonates.
Preparation 3: preparation 4 product (0.347g, 1.44mmol) join step 2 methanesulfonates (0.480g, 1.73mmol) in DMF (4.5mL), add subsequently NaH (60%, in oil, 0.082g, 4.04mmol).Stir 18h and with ethyl acetate extraction.Wash with water, dry (salt of wormwood) also concentrates.Utilize PTLC (5%CH 3OH/CH 2Cl 2, secondary treatment) purify, obtain the white solid target compound, MS:423 (M+1).
Adopt aforesaid method, preparation following compounds (embodiment 18-8 is a raw material with commercially available Biphenylylmethylcarbinol):
Embodiment 19
Figure A0181344900563
Step 1:4-bromobenzene ethanol (3.00g, 14.9mmol), triethylamine (2.68g, 19.2mmol), (0.180g, 1.47mmol) (2.45g is 16.3mmol) at CH with t-butyldimethylsilyl chlorine for Dimethylamino pyridine 2Cl 2Merge (75mL).Stir 1h, wash with water, dry (salt of wormwood) also concentrates.Go up chromatogram at silica gel (hexane) and purify, obtain silyl ether.
Step 2: to the compound of step 1 (0.300g, 0.95mmol) in dry toluene (15mL), add 2-(tributyl tin) pyridine (1.05g, 2.86mmol) and four (triphenylphosphines) close palladium (0.11g, 0.095mmol).Use purging with nitrogen gas, 120 ℃ of heating.Cooling is filtered through celite, washes with water then with ammonium chloride, salt solution.Dry (salt of wormwood) also concentrates.Go up chromatogram at silica gel (3～5% ethyl acetate-hexane) and purify, obtain the diaryl thing, MS314 (M+1).
Step 3: (0.180g, 0.57mmol) (1.0M 1.7mL) merges in THF (5.7mL) in THF the diaryl material of step 2 with TBAF.Stir 2h, with the saturated ammonium chloride washing, and with ethyl acetate extraction.Wash with water several times, dry (salt of wormwood) also concentrates, and obtains alcohol.
Step 4 and 5: as embodiment 18, step 2 and 3 is carried out like that, and the result obtains the white solid target compound, MS:423 (M+1).
Prepare following compounds similarly:
Figure A0181344900571
Embodiment 20
Figure A0181344900572
At-78 ℃, (0.055g is 0.13mmol) at CH to the product of embodiment 18 2Cl 2Between adding (1.5mL)-and CPBA (0.050g, 0.29mmol).Treat that it warms, stir 5h, and in succession with saturated sodium thiosulfate, 5% salt of wormwood and water washing.Dry (sodium sulfate) also concentrates.Adopt PTLC (10%CH 3OH/CH 2Cl 2) purify, obtain target compound, MS:439 (M+1).
Similarly, the product of embodiment 18-2 is at 0 ℃ or room temperature oxidation generation sulfoxide, MS:484 (M+1), or sulfone, MS:500 (M+1).
Embodiment 20-2
Figure A0181344900582
Embodiment 20-3
Embodiment 21
Figure A0181344900583
Preparation 6 product (0.104g, 0.30mmol), 4-methyl-benzenethiol (0.075g, 0.60mmol) and salt of wormwood (0.091g, 0.66mmol) merging in DMF (20mL).At 80 ℃ of heating 5h and concentrated.Distribute between ethyl acetate and water, use the salt water washing, dried over mgso also concentrates.From CH 3Recrystallization among the OH obtains target compound, MS:m/e=392 (M+1).
Prepare following compounds similarly:
Figure A0181344900584
Embodiment 22
Figure A0181344900591
Preparation 6 product (0.11g, 0.25mmol), 3, the 4-syringol (0.154g, 1.0mmol) and salt of wormwood (0.138g, 1.0mmol) merging in DMF (5mL).At 90 ℃ of heating 48h and concentrated.Distribute between ethyl acetate and water, with the washing of 1N sodium hydroxide, use the salt water washing then, dried over mgso also concentrates.(1.5%CH on silica gel 3OH/CH 2Cl 2) the chromatogram purification, obtain target compound, MS:m/e=422 (M+1).
Prepare following compounds similarly, MS:m/e=454 (M+1).
Figure A0181344900592
Embodiment 23
Figure A0181344900593
Step 1: at 5 ℃, to NaH (60% in oil, and 1.32g 33mmol) under agitation drips 3 in DMF (25mL), the 4-syringol (4.77g, 30mmol).0.5h after, adding 1.5-dibromo pentane (20.7g, 90mmol).Stir 2h and concentrated.(CH on silica gel 2Cl 2) the chromatogram purification, obtain monobromide, MS:m/e=303 (M+1).
Step 2: at 5 ℃, to NaH (60% in oil, 0.044g, 1.1mmol) in DMF (25mL), add preparation 1 product (0.241g, 1.1mmol).Behind the 05h, add the compound of step 1.Treat that it warms, stir 18h and concentrated.Distribute between ethyl acetate and water, with the washing of 1N sodium hydroxide, use the salt water washing then, dried over mgso also concentrates.(2%CH on silica gel 3OH/CH 2Cl 2) chromatogram purifies and from CH 3Recrystallization goes out suitable proportion among the CN, obtains target compound, MS:m/e=464M+1).
Embodiment 24
Figure A0181344900601
Step 1:1, (0.48mL, 3.8mmol) (0.66g 1.5mmol) merges in DMF (10mL) 4-two oxa-s-8-azaspiro (4,5) decane with the product for preparing 2.At 90 ℃ of heating 16h, treat its cooling, filter and with CH 3The OH washing obtains pale solid, MS:m/e411 (M+1).
Step 2: (0.476g 1.16mmol) heats 16h at 100 ℃ to the product of step 1 in acetone (10mL) and 5% hydrochloric acid (10mL).Cooling is with the saturated sodium bicarbonate neutralization and with 10%CH 3OH is at CH 2Cl 2Middle extraction.Dry (sal epsom) concentrates and is adopting CH 3OH-CH 2Cl 2Purify as chromatogram on the silica gel of eluent system, obtain white powder ketone, MS:m/e367 (M+1).
Step 3: (0.050g, 0.13mmol) (0.033g 0.39mmol) merges in pyridine (3mL) product of step 2 with neighbour-methyl oxyamine hydrochloride.Stir 16h and concentrated.Distribute between the solution in methylene dichloride at sodium bicarbonate (saturated) and 5% methyl alcohol.Dry (sal epsom), concentrate and adopt 5% methyl alcohol-methylene dichloride as the silica gel of eluent system on chromatogram purify, obtain the white solid target compound, MS:m/e396 (M+1).
Prepare following compounds similarly:
Figure A0181344900602
Embodiment ????R 11 ??MS，m/e
??24-2 ????-CH 2CH 3 ??410
??24-3 ????-CH 2CH 2CH 3 ??424
??24-4 ????-CH 2CHCH 2 ??422
??24-5 ????-C(CH 3) 3 ??438
??24-3 ????-C 6H 5 ??458
??24-4 ????-CH 2C 6H 5 ??472
Embodiment 25
Figure A0181344900611
Step 1:4-oxo-1-piperidine carboxylic acid benzyl ester (1.0g, 4.3mmol) and H 2(0.89g 13mmol) merges in pyridine (5mL) NOH.HCl.Stir 16h and concentrated.Distribute between sodium bicarbonate (saturated) and ethyl acetate, dry (sal epsom) also concentrates the output oxime.
Step 2: (0.44g, 1.8mmol) (0.20mL, 2.2mmol) (0.10g 2.7mmol) merges in DMF (8mL) product of step 1 with NaH with the 2-bromo-ethyl-methyl ether.Stir 16h and concentrated.Distribute between ammonium chloride (saturated) and ether, dry (sal epsom) also concentrates.Resistates carries out chromatogram with ethyl acetate-hexane wash-out on silica gel purifies, and obtains the alkylation oxime.
Step 3: (0.45g 1.47mmol) on 5%Pd/C (0.045g), in the ethyl acetate (25mL), stirs 6h to the product of step 2 under nitrogen atmosphere.Filter and concentrate, obtain amine.
Step 4: use the amine of the product treatment step 3 of preparation 2, as embodiment 24, step 1 obtains the white solid target compound, MS:m/e440 (M+1).
Embodiment 26
Triacetyl oxygen base sodium borohydride (0.083g, 0.39mmol) join embodiment 24, and the product of step 2 (0.050g, 0.13mmol), aniline (0.035mL, 0.39mmol) (0.045mL is 0.78mmol) in the mixture in ethylene dichloride (3mL) with AcOH.Stir 16h and at sodium bicarbonate (saturated) and 5% methyl alcohol at CH 2Cl 2In solution between distribute.Dry (sal epsom) also concentrates.Chromatogram purification (5%CH 3OH-CH 2Cl 2), obtain the white solid target compound, MS:m/e444 (M+1).
In a similar manner, preparation following compounds, MS:m/e445 (M+1).
Figure A0181344900622
Embodiment 27
Step 1:4-bromophenol (3.46g, 20.0mmol) with the 2-bromo-ethyl-methyl ether (2.82g, 30,0mmol) and salt of wormwood (8.30g, 60.0mmol) in acetone (50mL) merging.Reflux 16h, cooling is filtered and is concentrated.Chromatogram with 5% ethyl acetate/hexane wash-out on silica gel is purified, the ether of output clarification oily matter.At-78 ℃, to this ether (2.73g, 11.8mmol) in dry THF (50mL), add n-Butyl Lithium (solution in the 1.6M hexane, 7.4mL, 11.8mmol).Stir 10min, add 4-oxo-1-piperidine carboxylic acid benzyl ester (2.5g, 10.7mmol) solution in dry THF (5mL) then.Stir 2h and treat that it warms.Distribute between saturated ammonium chloride and ethyl acetate, dry (sal epsom) also concentrates.On silica gel, carry out chromatogram and purify, obtain alcohol with ethyl acetate/hexane (20: 80,40: 60 subsequently) wash-out.
Step 2: at-78 ℃, to the product of step 1 (0.386g, 1.0mmol) and triethyl silicane (0.80mL is 5.0mmol) at dry CH 2Cl 2(10mL), and the adding trifluoroacetic acid (0.38mL, 5.0mmol).Treat that it warms in 2h, between saturated sodium bicarbonate and methylene dichloride, distribute then.Dry (sal epsom) also concentrates.On silica gel, carry out chromatogram and purify, obtain reduzate, MS:m/e370 (M+1) with 20% ethyl acetate/hexane wash-out.
Step 3: (0.300g 0.758mmol) goes up in ethyl acetate (5mL) and methyl alcohol (5mL), stirs 2h under the nitrogen atmosphere at 5%Pd/C (0.030g) product of step 2.Filter and concentrate, obtain amine.
Step 4: the amine of step 3 to be preparing 2 product, and as at embodiment 24, step 1 is described to be handled, and the result obtains the white solid target compound, MS:m/e503 (M+1).
Embodiment 28
(0.020g, 0.044mmol) in ethanol (0.5mL), 0 ℃, (0.005g 0.13mmol) handles, and handles once more with same quantity behind 0.75h the product of embodiment 1-145 with sodium borohydride.After crossing 0.75h again, between methylene dichloride and saturated ammonium chloride, distribute.Dry (sodium sulfate) also concentrates.Utilize PTLC (10% ethanol/methylene) to purify, the result obtains the white solid target compound, MS:459 (M+1).
Embodiment 29
Figure A0181344900632
(0.020g, 0.044mmol) in pyridine (0.5mL), (0.011g 0.13mmol) handles the product of embodiment 1-145 with methoxy-amine hydrochloride.Stir 16h and concentrated.Between methylene dichloride and saturated sodium bicarbonate, distribute.Dry (sodium sulfate) also concentrates.Utilize PTLC (5% ethanol/methylene) to purify, the result obtains the white solid target compound, MS:486 (M+1).
Similarly, prepare the oxime 29-2 of two kinds of geometrical isomer forms of separating, every kind is white solid, MS:472 (M+1).
Figure A0181344900641
Owing to have adenosine A 2aReceptor antagonist activity, The compounds of this invention can be used for that treatment is depressed, cognitive function disease and nerve degeneration disease, for example, and parkinsons disease, as the senile dementia in the Alzheimer disease, and organic psychosis.Particularly, The compounds of this invention can improve because of the motor due to the nerve degeneration disease such as parkinsons disease impaired.
The medicament that can cooperate other that take to become known for treating parkinsons disease with compound of Formula I comprises: L-DOPA; The Dopamine HCL gaonist, for example, quinpirole, Ropinrole, pramipexole, pergolide and bromocriptine; The MAO-B inhibitor, for example, Selegiline and jumex; The DOPA decarboxylase inhibitor is as carbidopa and benserazide; And the COMT inhibitor, as, tolcapone and entacapone.Permission is used 1～3 kind of other medicament and compound of Formula I, and is preferably a kind of.
The A that the pharmacological activity of The compounds of this invention is measured by external and in vivo test 2aReceptor active and being determined.
The human body adenosine A 2aAnd A 1Receptor competitive binding assay
Membrane derived:
A 2a: human body A 2aThe Adenosine Receptors film, catalog number (Cat.No.) #RB-HA 2a, Receptor Biology (beltsville, MD).In film dilution buffer liquid (vide infra), be diluted to 17 μ g/100 μ L.
The chemical examination damping fluid:
Film dilution buffer liquid: Dulbecco ' s phosphate buffered saline buffer (Gibco/BRL)+10mM magnesium chloride.
The diluted chemical compound damping fluid: Dulbecco ' s phosphate buffered saline buffer (Gibco/BRL)+10mM magnesium chloride, and add 1.6mg/ml methylcellulose gum and 16%DMSO.Again prepare every day.
Part:
A 2a: [3H]-SCH58261, conventional synthetic, AmershamPharmacia Biotech company (Piscataway, New Jersey).Storage liquid prepares by 1nM in film dilution buffer liquid.Finally chemically examining with concentration is 0.5nM.
A 1: [3H]-DPCPX, AmershamPharmacia Biotech company (Piscataway, New Jersey).Storage liquid prepares by 2nM in film dilution buffer liquid.Finally chemically examining with concentration is 0.5nM.
A 2a: for measuring non-specific combination, add 100nM CGS15923 (RBI, Natick, MA).Work storage liquid prepares by 400nM in the diluted chemical compound damping fluid.
A 1: for measuring non-specific combination, add 100 μ M NECA (RBI, Natick, MA).Work storage liquid prepares by 400 μ M in the diluted chemical compound damping fluid.
Preparation 1mM compound storage liquid in 100%DMSO.In the diluted chemical compound damping fluid, dilute.The 10 kind concentration of test in 3 μ M～30pM scope are carried out.In the diluted chemical compound damping fluid, prepare 4 times to the working solution of ultimate density.
The chemical examination program:
Chemical examination is carried out on deep hole formula 96 orifice plates.The overall test volume is 200 μ L.Add 50 μ L diluted chemical compound damping fluids (total part combination) or 50 μ L CGS15923 working solution (A 2aNon-specific combination) or 50 μ L NECA working solution (A 1Non-specific combination) or 50 μ L pharmacy work solution.([3H]-SCH58261 is for A to add 50 μ L parts storage liquid 2a[3H]-DPCPX is for A 1).Add 100 μ L and contain the film of the dilution of suitable acceptor.Mixture is at incubated at room 90min.Adopt the Brandel cell harvester that solution is collected on the Packard GF/B screen plate.Add 45 μ L Microscint20 (Packard) and adopt Packard TopCountMicroscintillation rolling counters forward.By adopting iteration curve fitting procedure (Excel) to come the match displacement curve to determine IC 50Value.The Ki value is to adopt the Cheng-Prusoff equation to determine.
Haloperidol inductive catalepsy (rat)
Adopt male Sprague-Dawley rat (Charles River, Calco, Italy), weigh 175～200g.The catalepsy attitude is that (1mg/kg, sc) inductive are placed on this animal on the vertical barrier behind the 90min and test by subcutaneous administration dopamine-receptor antagonist haloperidol.In this test, rat is placed on the wire netting lid of 25 * 43 synthetic glass cages, and cage is put with testing table and spent angles into about 70.After being placed on rat on the barrier, four leg abductions are also stretched (" frog position ").Adopt the non-natural posture of this kind very crucial for the specificity of this catalepsy test.Putting first pawl institute's elapsed time (latent form of reduction) of moving away fully well from pawl is 120 seconds according to measuring maximum.
Accept the selectivity A of assessment 2aAdenosine antagonist is with the oral dose of 0.03～3mg/kg scope, and gives a mark to animal after 1 and 4 hour.
In the experiment that separates, measured control compound L-DOPA (25,50 and 100gm/kg, anti-tetanic effect ip).
The 6-OHDA damage of rat median forebrain bundle
Bull Sprague-Dawley rat (Charles River, Calco, Italy), body weight 270～300g is used in all experiments.Each cage of these rats is supported 4 as one group, and ad lib and drinking-water are under controlled temperature and be in 12h illumination/dark cycle.Perform the operation the day before yesterday, rat is tied to spend the night, but can freely drink water.
Implemented the 6-hydroxydopamine (6-OHDA) of median forebrain bundle and induced damage, method is according to people's such as Ungerstedt description (Brian Research, 1971,6-OHDA andCathecolamine Neurons, North Holland, Amsterdam, 101～127), and made slightly and to have revised.Briefly, before the 6-OHDA injection, (400mg/kg ip) anaesthetizes animal and (10mpk ip) handles 30min, so that blocking-up is by NE teleneuron picked-up toxin with Desipramine with Chloral Hydrate.Then, animal is placed in the stereotactic framework.With the skin reflexed on the skull bone and according to atlas (Pellegrino L.J., Pellegrino A.S. and Cushman A.J., AStereotaxic Altas of the Rat Brain, 1979, New York of people such as Pellegrino; Plenum press) measures the three-dimensional elements of a fix (2.2 the past craniums are to the rear portion (AP), and+1.5 the past craniums are to side (ML), and 7.8 from the endocranium to the belly (DV)).Then, the hole of cork drill being placed on the pin that this damage location top also will be contained on the Hamilton syringe in the skull bone drops among the left MFB.Subsequently, 8 μ g6-OHDA-HCl are dissolved in the 4 μ L salt solution, wherein contain 0.05% xitix, utilize filling pump to inject then with the constant flow rate of 1 μ L/1min as antioxidant.After crossing 5min again, extract pin, and the suture operation wound, and allow animal recover for 2 weeks.
In 2 weeks of damage back, (50mg/kg ip) adds that (25mg/kg ip), and selects rat according to the revolution (starting tests) that the complete offside of being finished with automatic tropometer mensuration at the 2h duration of test rolls to benserazide to take L-DOPA to rat.The rat of at least 200 the complete number of turns/2h of all not demonstrations is not included in the research without exception.
After the starting tests (maximum Dopamine Receptors supersensitivity), the rat reception test medicine of selection 3 days.New A 2aReceptor antagonist with the dosage level of 0.1～3mg/kg scope difference constantly (that is, 1,6,12h) oral, inject then sub-threshold dose L-DOPA (4-mpk, ip) add benserazide (4mpk, ip), the assessment behavior of rolling then.
Utilize above-mentioned testing sequence, the results are as follows to the preferred and/or representational compound of the present invention.
Showing of relevant The compounds of this invention in conjunction with test-results, A 2aThe Ki value equal 0.3～57nM, the Ki value of wherein preferred compound exhibits 0.3～5.0nM.
Selectivity is passed through A 1The Ki of acceptor is divided by A 2aThe Ki of acceptor determines.The selectivity of preferred compound of the present invention is between about 100～about 2000.
When rat is active with the anti-catalepsy of 1mg/kg oral test, the latent form decline 50-75% of preferred compound exhibits rat.
In the 6-OHDA damage test, the rat of oral 1mg/kg dosage preferred compound has finished 170～440 at 2-hour duration of test to be changeed.
In haloperidol-inductive catalepsy test, the combination table of general formula 1 compound sub-threshold dose and L-DOPA sub-threshold dose reveals the catalepsy obvious suppression, shows certain synergistic effect.In the 6-OHDA damage test, the experimental animal of the combination of the amount of taking under general formula 1 compound and the L-DOPA threshold shows obviously the higher offside ability of rolling.
For the compound pharmaceutical composition of being described by the present invention, inertia, drug acceptable carrier can be solid or liquid.But the preparation of solid form comprises powder, tablet discrete particles, capsule, cartridge bag and suppository.Powder and tablet can be made up of about 5～about 70% effective constituent.Suitable solid carrier is known in the art, for example, and magnesiumcarbonate, Magnesium Stearate, talcum powder, sugar, lactose.Tablet, powder, cartridge bag and capsule can be made and be fit to oral solid dosage form use.
Be preparation suppository, at first with low melt wax, glyceryl ester or cupraol fusion as lipid acid under agitation evenly spread to effective constituent wherein then.Fused homogeneous mixture is poured in the mould of size easy to use subsequently, thereby treats its cooling curing.
The preparation of liquid form comprises solution, suspensoid and emulsion.As water or water-propylene glycol solution without the stomach injection.
The liquid form preparation also comprises the solution of taking in the nose.
The aerosol preparations that be fit to suck can comprise the solid of solution and powder type, can with drug acceptable carrier, combine as inertia pressurized air.
Also comprise, plan to be converted in the short period of time before use oral or without the solid form preparation of the liquid form preparation of stomach administration.This kind liquid form comprises solution, suspensoid and emulsion.
But The compounds of this invention is percutaneous dosing also.Transdermal composition can be taked emulsifiable paste, astringent, aerosol and/or emulsion form, and can be included in matrix or liquid storage type in the skin plaster, as this area done traditionally for this purpose.
Preferably, this compound oral administration.
Preferably, this pharmaceutical preparation is made unit dosage form.With this kind form, preparation is subdivided into and comprises appropriate amount effective constituent, for example, is the unitary dose of the significant quantity activeconstituents that meets the requirements of purpose.
The quantity of unit dose formulations formula of I active compound can be between about 0.1mg～1000mg, and more preferably from about 1mg～300mg decides according to concrete purposes.
The actual dosage that adopts is different according to the seriousness of patient's the requirement and the treatment state of an illness.The determining of appropriate dosage in light of the circumstances belongs to the content in the general technology scope.Usually, treat from the dosage of the optimal dose that is lower than compound.Subsequently, dosage increases gradually with little increment, until the best effect that reaches under particular case.Be convenient meter, if require, total per daily dose can mark part administration in a day.
The administration quantity of The compounds of this invention and drug acceptable salt thereof and frequency will be considered such as patient age, state and body weight according to the clinician of nurse and handle the judgement that the severity of symptom does and regulate.The typical recommended doses of compound of Formula I is that oral 10mg～2000mg/ day preferably 10～1000mg/ day, divides and takes for 2～4 times, is beneficial to the alleviation of central nervous system disease such as parkinsons disease.When taking the time spent orally at this dosage range, this compound is atoxic.
The dosage and the dosage instructions about how to take medicine of other medicaments of treatment parkinsons disease are determined that by the clinician for example, dosage and dosage instructions about how to take medicine that consideration is ratified in the inset are considered patient age, sex and state and disease severity in a complete set of.Estimate, when compound of Formula I and other medicament administered in combination, compare, just will play curative effect than the composition of low dosage with the dose of components of taking of monotherapy.
Be the example that comprises the pharmaceutical dosage forms of The compounds of this invention below.Those skilled in the art will recognize that these dosage forms can make an amendment, so that comprise compound of Formula I and another kind of medicament.The scope of the present invention with regard to its pharmaceutical composition is not limited to given example.
The example of pharmaceutical dosage forms
Embodiment A-tablet
Numbering Composition The mg/ sheet The mg/ sheet
??1. Active compound ????100 ????500
??2. Lactose USP ????122 ????113
??3. Cereal starch, food grade, 10% pasty state in pure water ????30 ????40
??4. Cereal starch, food grade ????45 ????40
??5. Magnesium Stearate ???? 3 ???? 7
Add up to ????300 ????700
Manufacture method
Numbering 1 is suitably being mixed 10～15min in the mixing machine with 2 component.With the component granulation of mixture with numbering 3.Necessary, this particle take advantage of wet pulverized scalping (for example, 1/4 inch, 0.63cm).Wet pellet drying.Dried particles sieves, and needs, and mixes and mix 10～15min with the component of numbering 4 then.The component that adds numbering 5, remix 1～3min.Mixture is placed on is pressed into suitable size and weight on the suitable tabletting machine.
Embodiment B-capsule
Numbering Composition The mg/ capsule The mg/ capsule
????1. Active compound ????100 ?????500
????2. Lactose USP ????106 ?????123
????3. Cereal starch, food grade ????40 ?????70
????4. Magnesium Stearate NF ???? 7 ????? 7
Add up to ????253 ?????700
Manufacture method
The component of numbering 1,2 and 3 is suitably being mixed 10～15min in the mixing machine.Add the component of numbering 4 and mix 1～3min.On suitable encapsulate machine, mixture is filled in the suitable two-piece type hard gelatin capsule.
Though just the specific embodiments that provides is above described the present invention, its modifications and variations scheme it will be apparent to those skilled in the art that.All these substitute, modification and conversion scheme all belong within the scope of the invention.

Claims (15)

1. the compound that has following structural formula Or its drug acceptable salt, wherein
R is R 1-furyl, R 1-thienyl, R 1-pyridyl, R 1-pyridyl N-oxide compound, R 1-oxazolyls, R 10-phenyl, R 1-pyrryl or C 4～C 6Cycloalkenyl group;
X is C 2～C 6Alkylidene group or-C (O) CH 2-;
Y is-N (R 2) CH 2CH 2N (R 3)-,-OCH 2CH 2N (R 2)-,-O-,-S-,-CH 2S-,-(CH 2) 2-NH-or
And
Z is R 5-phenyl, R 5-phenyl (C 1～C 6) alkyl, R 5-heteroaryl, diphenyl methyl, R 6-C (O)-, R 6-SO 2-, R 6-OC (O)-, R 7-N (R 8)-C (O)-, R 7-N (R 8)-C (S)-,
Figure A0181344900023
, phenyl-CH (OH)-or phenyl-C (=NOR 2)-; Perhaps working as Q is
Figure A0181344900024
The time, Z also can be phenyl amino or pyridinylamino; Perhaps
Z with Y is
R 1Be 1～3 substituting group, be independently selected from hydrogen, C 1～C 6-alkyl ,-CF 3, halogen ,-NO 2,-NR 12R 13, C 1～C 6Alkoxyl group, C 1～C 6Alkylthio, C 1～C 6Alkyl sulphinyl and C 1～C 6Alkyl sulphonyl;
R 2With R 3Be independently selected from hydrogen and C 1～C 6Alkyl;
M and n are 2～3 independently; Or
Figure A0181344900032
Q is
R 4Be 1～2 substituting group, be independently selected from hydrogen and C 1～C 6Alkyl or two R on same carbon atom 4Substituting group can form=O;
R 5Be 1～5 substituting group, be independently selected from hydrogen, halogen, C 1～C 6-alkyl, hydroxyl, C 1～C 6Alkoxyl group ,-CN, two-((C 1～C 6) alkyl) amino ,-CF 3,-OCF 3, ethanoyl ,-NO 2, hydroxyl (C 1～C 6) alkoxyl group, (C 1～C 6)-alkoxyl group (C 1～C 6) alkoxyl group, two-((C 1～C 6)-alkoxyl group) (C 1～C 6) alkoxyl group, (C 1～C 6)-alkoxyl group-(C 1～C 6) alkoxyl group-(C 1～C 6)-alkoxyl group, carboxyl (C 1～C 6)-alkoxyl group, (C 1～C 6)-carbalkoxy (C 1～C 6) alkoxyl group, (C 3～C 6) cycloalkyl (C 1～C 6) alkoxyl group, two ((C 1～C 6)-alkyl) amino (C 1～C 6) alkoxyl group, morpholinyl, (C 1～C 6) alkyl-SO 2-, (C 1～C 6) alkyl-SO-(C 1～C 6) alkoxyl group, THP trtrahydropyranyl oxygen base, (C 1～C 6) alkyl-carbonyl (C 1～C 6)-alkoxyl group, (C 1～C 6)-carbalkoxy, (C 1～C 6) alkyl-carbonyl oxygen base (C 1～C 6)-alkoxyl group ,-SO 2NH 2, phenoxy group, Or adjacent R 5Substituting group lumps together and is-O-CH 2-O-,-O-CH 2CH 2-O-,-O-CF 2-O-or-O-CF 2CF 2-O-and the carbon atom that is connected with them constitute a ring;
R 6Be (C 1～C 6) alkyl, R 5-phenyl, R 5-phenyl (C 1～C 6) alkyl, thienyl, pyridyl, (C 3～C 6)-cycloalkyl, (C 1～C 6) alkyl-OC (O)-NH-(C 1～C 6) alkyl-, two-((C 1～C 6) alkyl) aminomethyl or (C 1-C 6) alkyl
R 7Be (C 1～C 6) alkyl, R 5-phenyl or R 5-phenyl (C 1～C 6) alkyl;
R 8Be hydrogen or C 1～C 6Alkyl; Perhaps R 7With R 8Be together-(CH 2) p-A-(CH 2) q, wherein p and q are 2 or 3 independently, A be chemical bond ,-CH 2-,-S-or-O-and the nitrogen-atoms that is connected with them constitute a ring;
R 9Be 1～2 group, be independently selected from hydrogen, C 1～C 6Alkyl, hydroxyl, C 1～C 6Alkoxyl group, halogen ,-CF 3(C 1～C 6) alkoxyl group (C 1～C 6) alkoxyl group;
R 10Be 1～5 substituting group, be independently selected from hydrogen, halogen, C 1～C 6Alkyl, hydroxyl, C 1～C 6Alkoxyl group ,-CN ,-NH 2, C 1～C 6Alkylamino, two-((C 1～C 6) alkyl) amino ,-CF 3,-OCF 3With-S (O) 0～2(C 1～C6) alkyl;
R 11Be hydrogen, C 1～C 6Alkyl, phenyl, benzyl, C 2～C 6Alkenyl, C 1～C 6Alkoxyl group (C 1～C 6) alkyl, two-((C 1～C 6) alkyl) amino (C 1～C 6) alkyl, pyrrolidyl (C 1～C 6) alkyl or piperidino-(1-position only) (C 1～C 6) alkyl;
R 12Be hydrogen or C 1～C 6Alkyl; And
R 13Be (C 1～C 6) alkyl-C (O)-or (C 1～C 6) alkyl-SO 2-.
2. the compound of claim 1, wherein R is R 1-furyl.
3. the compound of claim 1, wherein X is C 2～C 6Alkylidene group.
4. the compound of claim 1, wherein Y is
5. the compound of claim 1, wherein Q is Or
Figure A0181344900043
, m and n each naturally 2, and R 4Be H.
6. the compound of claim 1, wherein Z is R 5-phenyl, R 5-heteroaryl, R 6-C (O)-or R 6-SO 2-.
7. the compound of claim 6, wherein R 5Be H, halogen, C 1～C 6Alkyl, C 1～C 6Alkoxyl group, hydroxyl (C 1～C 6) alkoxyl group or (C 1～C 6) alkoxyl group (C 1～C 6) alkoxyl group, and R 6Be R 5-phenyl.
8. the compound of claim 1 is selected from the compound of following structural, Wherein R and Z-Y according to the form below are stipulated:
9. the pharmaceutical composition that in drug acceptable carrier, comprises claim 1 compound for the treatment of significant quantity.
10. the compound of claim 1 is used to prepare the application of the medicine for the treatment of depression, cognitive illnesses, nerve degeneration disease or apoplexy.
11. compound for preparing general formula I I
Figure A0181344900061
Method, wherein R is R 1-furyl, R 1-thienyl, R 1-pyridyl, R 1-pyridyl N-oxide compound, R 1-oxazolyls, R 10-phenyl, R 1-pyrryl or C 4～C 6Cycloalkenyl group; And
R 1Be 1～3 substituting group, be independently selected from hydrogen, C 1～C 6-alkyl ,-CF 3, halogen ,-NO 2,-NR 12R 13, C 1～C 6Alkoxyl group, C 1～C 6Alkylthio, C 1～C 6Alkyl sulphinyl and C 1～C 6Alkyl sulphonyl;
R 10Be 1～5 substituting group, be independently selected from hydrogen, halogen, C 1～C 6Alkyl, hydroxyl, C 1～C 6Alkoxyl group ,-CN ,-NH 2, C 1～C 6Alkylamino, two-((C 1～C 6) alkyl) amino ,-CF 3,-OCF 3With-S (O) 0～2(C 1～C 6) alkyl;
R 12Be hydrogen or C 1～C 6Alkyl; And
R 13Be (C 1～C 6) alkyl-C (O)-or (C 1～C 6) alkyl-SO 2-; Comprise:
(1) 2-amino-4, the 6-dihydroxy-pyrimidine
With POCl 3Handle in dimethyl formamide, the result obtains 2-amino-4,6-dichloro pyrimidine-5-formaldehyde
Figure A0181344900063
(2) aldehyde VII is H with the general formula 2The hydrazides of N-NH-C (O)-R is handled, and wherein R is by top regulation, and the result obtains
Figure A0181344900071
(3) intermediate of general formula VIII is handled with hydrazine hydrate and is generated the pyrazolo ring, thereby obtains the intermediate of general formula I X
(4) reset the desired general formula I I compound of generation by dehydration.
12. compound for preparing general formula I I Method, wherein R is R 1-furyl, R 1-thienyl, R 1-pyridyl, R 1-pyridyl N-oxide compound, R 1-oxazolyls, R 10-phenyl, R 1-pyrryl or C 4～C 6Cycloalkenyl group; And
R 1Be 1～3 substituting group, be independently selected from hydrogen, C 1～C 6-alkyl ,-CF 3, halogen ,-NO 2,-NR 12R 13, C 1～C 6Alkoxyl group, C 1～C 6Alkylthio, C 1～C 6Alkyl sulphinyl and C 1～C 6Alkyl sulphonyl;
R 10Be 1～5 substituting group, be independently selected from hydrogen, halogen, C 1～C 6Alkyl, hydroxyl, C 1～C 6Alkoxyl group ,-CN ,-NH 2, C 1～C 6Alkylamino, two-((C 1～C 6) alkyl) amino ,-CF 3,-OCF 3With-S (O) 0～2(C 1～C 6) alkyl;
R 12Be hydrogen or C 1～C 6Alkyl; And
R 13Be (C 1～C 6) alkyl-C (O)-or (C 1～C 6) alkyl-SO 2-;
Comprise: with the compound of general formula I X
Be converted into desired general formula I I compound by the dehydration rearrangement.
13. compound for preparing general formula III a
Figure A0181344900081
Method, wherein R is R 1-furyl, R 1-thienyl, R 1-pyridyl, R 1-pyridyl N-oxide compound, R 1-oxazolyls, R 10-phenyl, R 1-pyrryl or C 4～C 6Cycloalkenyl group; And
R 1Be 1～3 substituting group, be independently selected from hydrogen, C 1～C 6-alkyl ,-CF 3, halogen ,-NO 2,-NR 12R 13, C 1～C 6Alkoxyl group, C 1～C 6Alkylthio, C 1～C 6Alkyl sulphinyl and C 1～C 6Alkyl sulphonyl;
R 10Be 1～5 substituting group, be independently selected from hydrogen, halogen, C 1～C 6Alkyl, hydroxyl, C 1～C 6Alkoxyl group ,-CN ,-NH 2, C 1～C 6Alkylamino, two-((C 1～C 6) alkyl) amino ,-CF 3,-OCF 3With-S (O) 0～2(C 1～C 6) alkyl;
R 12Be hydrogen or C 1～C 6Alkyl; And
R 13Be (C 1～C 6) alkyl-C (O)-or (C 1～C 6) alkyl-SO 2-;
Comprise:
(1) muriate of general formula VIII
With general formula HO-(CH 2) r-NHNH 2The hydroxyalkyl hydrazine handle, wherein r is 2～6, the result obtains
(2) intermediate of general formula X is reset and cyclisation by dehydration, and the result obtains the three ring intermediates of general formula X I And
(3) oxy-compound of general formula X I is converted into the bromide of general formula III a.
14. a pharmaceutical composition, other are used for the treatment of the combination of the medicament of parkinsons disease to comprise the compound of the claim 1 for the treatment of significant quantity and 1～3 kind in drug acceptable carrier.
15. the compound of claim 1 and 1～3 kind of other medicament that is used for the treatment of parkinsons disease combine and prepare the application of the medicine for the treatment of parkinsons disease.
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CN112469722A (en) * 2018-07-23 2021-03-09 百济神州有限公司 Pyrazolo-triazolopyrimidine derivatives as A2A receptor antagonists
CN110742893B (en) * 2018-07-23 2024-04-05 百济神州(北京)生物科技有限公司 Methods of treating cancer with A2A receptor antagonists
CN111072675A (en) * 2019-12-12 2020-04-28 广东东阳光药业有限公司 Nitrogen-containing fused tricyclic derivatives and uses thereof

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